Mechanisms of Resistance to Tyrosine Kinase Inhibitors in ROS1 Fusion-Positive Nonsmall Cell Lung Cancer.

BACKGROUND: ROS1 fusion-positive (ROS1+) nonsmall cell lung cancer (NSCLC) patients are highly sensitive to tyrosine kinase inhibitor (TKI) treatments. However, acquired TKI resistance remains the major hurdle preventing patients from experiencing prolonged benefits. METHODS: 107 advanced or metastatic ROS1+ NSCLC patients who progressed on crizotinib and lorlatinib were recruited. Tissue and plasma samples were collected at baseline (N = 50), postcrizotinib (N = 91), and postlorlatinib (N = 21), which were all subject to the 139-gene targeted next-generation DNA sequencing. Molecular dynamics modeling was performed to investigate the effects of ROS1 mutations on binding to different TKIs. RESULTS: In patients with postcrizotinib and postlorlatinib samples, an accumulation of on- and off-target resistance alterations after multiple TKI treatments was observed. ROS1 G2032R and MET amplification were the most common on-target and off-target alterations, respectively. Patients with CD74-ROS1 and SLC34A2-ROS1 had longer progression-free survival (PFS) (P < 0.001) and higher rates of resistance mutations (on-target, P = 0.001; off-target, P = 0.077) than other ROS1 fusion variants following crizotinib treatment. Ten distinct on-target resistance mutations were detected after TKI therapies, of which 4 were previously unreported (ROS1 L2010M, G1957A, D1988N, L1982V). Molecular dynamics simulations showed that all 4 mutations were refractory to crizotinib, while G1957A, D1988N, and L1982V were potentially sensitive to lorlatinib and entrectinib. CONCLUSIONS: This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

Plasma extracellular vesicle transcriptomics identifies CD160 for predicting immunochemotherapy efficacy in lung cancer.

Better biomarkers are needed to improve the efficacy of immune checkpoint inhibitors in lung adenocarcinoma (LUAD) treatment. We investigated the plasma extracellular vesicle (EV)-derived long RNAs (exLRs) in unresectable/advanced LUAD to explore biomarkers for immunochemotherapy. Seventy-four LUAD patients without targetable mutations receiving first-line anti-programmed cell death 1 (PD-1) immunochemotherapy were enrolled. Their exLRs were profiled through plasma EV transcriptome sequencing. Biomarkers were analyzed against response rate and survival using pre- and post-treatment samples in the retrospective cohort (n = 36) and prospective cohort (n = 38). The results showed that LUAD patients demonstrated a distinct exLR profile from the healthy individuals (n = 56), and T-cell activation-related pathways were enriched in responders. Among T-cell activation exLRs, CD160 exhibited a strong correlation with survival. In the retrospective cohort, the high baseline EV-derived CD160 level correlated with prolonged progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.005), with an area under the curve (AUC) of 0.784 for differentiating responders from non-responders. In the prospective cohort, the CD160-high patients also showed prolonged PFS (P = 0.003) and OS (P = 0.014) and a promising AUC of 0.648. The predictive value of CD160 expression was validated by real-time quantitative PCR. We also identified the dynamics of EV-derived CD160 for monitoring therapeutic response. The elevated baseline CD160 reflected a higher abundance of circulating NK cells and CD8+ -naïve T cells, suggesting more active host immunity. In addition, increased CD160 levels of tumors also correlated with a favorable prognosis in LUAD patients. Together, plasma EV transcriptome analysis revealed the role of the baseline CD160 level and early post-treatment CD160 dynamics for predicting the response to anti-PD-1 immunochemotherapy in LUAD patients.

Rh-Endostatin Plus Irinotecan/Cisplatin as Second-Line Therapy for Advanced Esophageal Squamous Cell Carcinoma: An Open-Label, Phase II Study.

BACKGROUND: This open-label, phase II study aimed to investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) plus irinotecan/cisplatin as second-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: Eligible patients received 15mg/m2 Rh-endostatin as a continuous intravenous pump infusion (7 continuous days), 60mg/m2 irinotecan (days 1 and 8), and 60mg/m2 cisplatin (day 1) every 3 weeks. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 50 patients were assessable for efficacy and safety analysis. The median follow-up was 10.97 months (95%CI: 7.03-19.42) as the data cutoff. Median PFS was 4.01 months (95% CI: 3.19-5.49), and median overall survival (OS) was 12.32 months (95% CI: 8.21-17.45); 13 (26%; 95% CI: 15.87-39.55) of 50 patients had an objective response, and 31 (62%; 95% CI: 48.15-74.14) had disease control. Grade 3 or greater treatment-related adverse events (AEs) occurred in 12 (24.0%) patients, and no deaths were reported. The common grade 3 or greater AEs were leucopenia (18.0%) and neutropenia (16.0%). Five (10%) patients discontinued treatment because of AEs. CONCLUSION: Rh-endostatin plus irinotecan/cisplatin showed promising anti-tumor activity in advanced ESCC patients with a good safety profile in the second-line setting, which warrants further study in this population. (ClinicalTrials.gov identifier: NCT03797625).

A Phase II Study of Apatinib in Patients with Chemotherapy-Refractory Esophageal Squamous Cell Carcinoma (ESO-Shanghai 11).

LESSONS LEARNED: Apatinib has potential as an effective and safe second-line or higher treatment for patients with chemotherapy-refractory esophageal squamous cell carcinoma (ESCC). Clinical safety is of potential concern when administering apatinib to patients with uncontrolled esophageal lesions or severe invasion of trachea, bronchi, or major blood vessels. To the best of the authors' knowledge, this is the first prospective phase II study to investigate apatinib for patients with chemotherapy-refractory ESCC. Apatinib could provide an alternative option for ESCC after first-line or higher therapy in carefully selected patients. BACKGROUND: The aim of this study was to evaluate the efficacy and adverse effects of the oral vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitor apatinib in patients with chemotherapy-refractory esophageal squamous cell carcinoma (ESCC). METHODS: We enrolled patients with chemotherapy-refractory ESCC. All patients received continuous apatinib 500 mg once daily. RESULTS: Between July 2017 and August 2018, 40 patients were recruited, of whom 5 (12.5%) had uncontrolled primary tumors. Additionally, three patients with partial response (PR) and 23 with stable disease (SD) were observed for overall response rate (ORR) of 7.5% and disease control rate (DCR) of 65.0%. Median progression-free survival (PFS) was 3.8 months (95% confidence interval [CI], 2.2-5.4); median overall survival (OS) was 5.8 months (95% CI, 3.2-8.4). Common adverse effects were fatigue (15%), hypertension (12.5%), and palmar-plantar erythrodysesthesia syndrome (10%). Two cases of death from massive bronchopulmonary hemorrhage were observed, and esophageal fistula occurred in another two patients. Notably, both patients with esophageal fistula and one patient with massive fatal bronchopulmonary hemorrhage were individuals with uncontrolled primary tumors (3/5, 60%). Fatal bronchopulmonary hemorrhage in a second patient was associated with major blood vessel invasion. CONCLUSION: Apatinib has potential as an effective and safe treatment for patients with chemotherapy-refractory ESCC whose primary tumors are controlled and without severe invasion of trachea, bronchi, or major blood vessels.

Transcription factor RUNX3 promotes CD8+ T cell recruitment by CCL3 and CCL20 in lung adenocarcinoma immune microenvironment.

Considering the existence of immune-desert in tumor microenvironment, the clinical efficacy of immunotherapy for lung adenocarcinoma is limited. This study aims to investigate the ability of transcription factors in regulating tumor immune microenvironment in lung adenocarcinoma. RNA-seq data were collected from the The Cancer Genome Atlas database. The relationships between transcription factors and immune infiltrates were assessed. Runt-related transcription factor 3 (RUNX3)-associated immune pathways were investigated by the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and Gene set enrichment analysis. Upregulated chemokines in the RUNX3-overexpressed cell line were determined by quantitative real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay. These chemokines were further confirmed in RUNX3-downregulated cell lines. Immunochemistry was conducted to determine the expression of RUNX3, CCL3, CCL20, and the numbers of CD8+ T lymphocytes in human lung cancer tissues. Chemokine receptors in CD8+ T cells were explored by flow cytometry and immunofluorescence. T cell recruitment was investigated by transwell assay. After screening 406 transcription factors, RUNX3 was found strongly correlated T cells, cytotoxic lymphocytes, and CD8+ T cells. RUNX3 was associated with a variety of immunomodulators, including LAG3, CTLA-4, PD-1, and TIGIT. More importantly, RUNX3 was involved in immune-related pathways, especially immune cell migration-related pathways. Further investigation exhibited RUNX3 could upregulate CCL3 and CCL20 whose receptors CCR5 and CCR6 were upregulated in CD8+ effector T cells, while downregulation of RUNX3 decreased the expression of CCL3 and CCL20 and the infiltration of CD8+ T cells in RUNX3-downregulated lung cancer cell lines. Immunochemistry exhibited positive correlations of RUNX3 with CCL3 and CD8+ T cells in clinical lung adenocarcinoma samples. The chemotaxis assay proved RUNX3 could promote CD8+ T cell recruitment by upregulating CCL3 and CCL20. This study unearths RUNX3 related molecular mechanisms of tumor immune microenvironment and may reverse the immune-desert condition in lung adenocarcinoma and be combined with immune checkpoint blockade and adoptive cell therapy.

USP53 promotes apoptosis and inhibits glycolysis in lung adenocarcinoma through FKBP51-AKT1 signaling.

Despite an overall decline in the incidence of new cases, lung adenocarcinoma continues to be a leading cause of cancer death worldwide. Due to lack of gene expression signatures for risk and prognosis stratification of lung adenocarcinoma, identifying novel molecular biomarkers and therapeutic targets may potentially improve lung adenocarcinoma prognosis and treatment. In the current study, we investigate the role of USP53 in lung adenocarcinoma. Bioinformatics analysis, quantitative reverse transcription polymerase chain reaction, and Western blot were employed to examine patterns of gene expression in human lung adenocarcinoma database, patient samples, and cancer cell lines. Stable cell lines were produced by transducing with USP53 overexpression vector or short hairpin RNA targeting USP53 in the presence and absence of AKT pathway inhibitor LY294002. Functional assays were carried out to examine the impact of USP53 and AKT pathway on lung adenocarcinoma cell viability, apoptosis, and glycolysis in vitro, as well as tumor growth in vivo. The correlation between USP53 and FKBP51 was measured by coimmunoprecipitation and ubiquitination assay. Decreased USP53 levels are a reliable marker of lung adenocarcinoma across published datasets, clinical samples, and cell culture lines. Low USP53 expression is linked to decreased apoptosis and increased metabolic activity, suggesting it acts as a tumor suppressor. USP53 regulates cell apoptosis and glycolysis through the AKT1 pathway. Mechanistically, USP53 deubiquitinates FKBP51, which in turn dephosphorylates AKT1, and ultimately inhibits tumor growth in lung adenocarcinoma. Taken together, our study establishes USP53 as a novel regulator of AKT1 pathway with an important role in tumorigenesis in lung adenocarcinoma.

Identification of an immune signature predicting prognosis risk of patients in lung adenocarcinoma.

BACKGROUND: Lung cancer has become the most common cancer type and caused the most cancer deaths. Lung adenocarcinoma (LUAD) is one of the major type of lung cancer. This study aimed to establish a signature based on immune related genes that can predict patients' OS for LUAD. METHODS: The expression data of 976 LUAD patients from The Cancer Genome Atlas database (training set) and the Gene Expression Omnibus database (four testing sets) and 1534 immune related genes from the ImmPort database were used for generation and validation of the signature. The glmnet Cox proportional hazards model was used to find the best gene model and construct the signature. To assess the independently prognostic ability of the signature, the Kaplan-Meier survival analysis and Cox's proportional hazards model were performed. RESULTS: A gene model consisting of 30 immune related genes with the highest frequency after 1000 iterations was used as our signature. The signature demonstrated robust prognostic ability in both training set and testing set and could serve as an independent predictor for LUAD patients in all datasets except GSE31210. Besides, the signature could predict the overall survival (OS) of LUAD patients in different subgroups. And this signature was strongly associated with important clinicopathological factors like recurrence and TNM stage. More importantly, patients with high risk score presented high tumor mutation burden. CONCLUSIONS: This signature could predict prognosis and reflect the tumor immune microenvironment of LUAD patients, which can promote individualized treatment and provide potential novel targets for immunotherapy.

Application value of nomogram and prognostic factors of gastric cancer patients who underwent D2 radical lymphadenectomy.

BACKGROUND: The aim of this study was to explore the prognostic factors and establish a nomogram to predict the long-term survival of gastric cancer patients. METHODS: The clinicopathological data of 421 gastric cancer patients, who were treated with radical D2 lymphadenectomy by the same surgical team between January 2009 and March 2017, were collected. The analysis of long-term survival was performed using Cox regression analysis. Based on the multivariate analysis results, a prognostic nomogram was formulated to predict the 5-year survival rate probability. RESULTS: In the present study, the total overall 3-year and 5-year survival rates were 58.7 and 45.8%, respectively. The results of the univariate Cox regression analysis revealed that tumor staging, tumor location, Borrmann type, the number of lymph nodes dissected, the number of lymph node metastases, positive lymph nodes ratio, lymphocyte count, serum albumin, CEA, CA153, CA199, BMI, tumor size, nerve invasion, and vascular invasion were prognostic factors for gastric cancer (all, P < 0.05). However, merely tumor staging, tumor location, positive lymph node ratio, CA199, BMI, tumor size, nerve invasion, and vascular invasion were independent risk factors, based on the results of the multivariate Cox regression analysis (all, P < 0.05). The nomogram based on eight independent prognostic factors revealed a well-degree of differentiation with a concordance index of 0.76 (95% CI: 0.72-0.79, P < 0.001), which was better than the AJCC-7 staging system (concordance index = 0.68). CONCLUSION: The present study established a nomogram based on eight independent prognostic factors to predict long-term survival in gastric cancer patients. The nomogram would be beneficial for more accurately predicting the prognosis of gastric cancer, and provide important basis for making individualized treatment plans following surgery.

Weekly albumin-bound paclitaxel/cisplatin versus gemcitabine/cisplatin as first-line therapy for patients with advanced non-small-cell lung cancer: A phase II open-label clinical study.

OBJECTIVE: The aim of this trial was to compare both the efficacy and the safety of a weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus cisplatin vs. gemcitabine plus cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: A total of 84 participants received either 100 mg/m2 nab-paclitaxel each week on d 1, 8 and 15 of a 28 day cycle, as well as cisplatin 75 mg/m2 on d 1 every three weeks (nab-TP arm); or gemcitabine 1,000 mg/m2 on d 1 and 8, plus cisplatin 75 mg/m2 on d 1 every three weeks (GP arm). The primary end point was progression-free survival (PFS). The secondary end points were overall response rate (ORR) and overall survival (OS). RESULTS: According to our analysis, the median PFS was 4.8 months for the nab-TP arm vs. 5.2 months for the GP arm (P=0.55). Analysis showed the median OS was 14.6 months for participants who were in the nab-TP arm vs. 15.1 months for those in the GP arm (P=0.94). Besides, nab-TP showed OS advantages over GP in patients harboring epidermal growth factor receptor (EGFR) mutation (26.7 vs. 15.3 months, P=0.046) and patients with a performance status of 0 (23.5 vs. 14.7 months, P=0.020). It was found that incidences of drug-related grade 3 or 4 toxicities were comparable between the two treatment arms. CONCLUSIONS: Therefore, it can be seen that weekly nab-TP treatment has a similar efficacy and tolerability to GP treatment for patients who are undergoing their first-line treatment for NSCLC. It could be that survival differences among platinum doublets in the context of both EGFR mutation and performance status have the potential to be the basis for our further clinical trials.

Phase II study of doxorubicin and thalidomide in patients with refractory aggressive fibromatosis.

Background To evaluate the efficacy and safety of doxorubicin (ADM) combined with thalidomide (THA) as a first-line treatment for patients with refractory aggressive fibromatosis (AF). Patients and Methods Eligible patients were treated with ADM 30 mg/m2 on days 1-2 and THA 200 mg nightly on days 1-21 every 3 weeks for a maximum of six cycles. THA was then continued for a total of 1 year. The primary end point was response rate (RR). Results Fifteen patients were enrolled in the study. No patient had a complete response, but five patients had partial responses, resulting in a RR of 33%. Eight patients (53%) had stable disease and two patients (13%) had progressive disease, and the disease control rate was 87%. The median progression free survival (mPFS) was 20.6 months (95% confidence interval, 14.5-26.7 months). Patients with below normal baseline serum albumin levels had significantly inferior mPFS compared with those with normal baseline serum albumin (1.4 months versus 23.7 months, P = 0.045). Grade 3/4 toxicities included leukopenia (33%), neutropenia (60%), febrile neutropenia (7%), nausea (7%), and vomiting (6.6%). Conclusions ADM plus THA was well-tolerated and effective as a first-line treatment for patients with refractory AF. However, patients with hypoalbuminemia at baseline had inferior clinical outcomes, and further studies are needed to investigate this issue.

Construction and Comprehensive Analysis for Dysregulated Long Non-Coding RNA (lncRNA)-Associated Competing Endogenous RNA (ceRNA) Network in Gastric Cancer.

Long non-coding RNA (lncRNA) is a kind of non-coding RNA with transcripts more than 200 bp in length. LncRNA can interact with the miRNA as a competing endogenous RNA (ceRNA) to regulate the expression of target genes, which play a significant role in the initiation and progression of tumors. In this study, we explored the functional roles and regulatory mechanisms of lncRNAs as ceRNAs in gastric cancer, and their potential implications for prognosis. The lncRNAs, miRNAs, and mRNAs expression profiles of 375 gastric cancer tissues and 32 non-tumor gastric tissues were downloaded from The Cancer Genome Atlas (TCGA) database. Differential expression of RNAs was identified using the DESeq package. Survival analysis was estimated based on Kaplan-Meier curve analysis. KEGG pathway analysis was performed using KOBAS 3.0. The dysregulated lncRNA-associated ceRNA network was constructed in gastric cancer based on bioinformatics generated from miRcode and miRTarBase. A total of 237 differentially expressed lncRNAs and 198 miRNAs between gastric cancer and matched normal tissues were screened in our study with thresholds of |log2FC| >2 and adjusted P value <0.01. Eleven discriminatively expressed lncRNAs may be correlated with tumorigenesis of gastric cancer. Seven out of 11 dysregulated lncRNA were found to be significantly associated with overall survival in gastric cancer (P value <0.05). The newly identified ceRNA network includes 11 gastric cancer-specific lncRNAs, 9 miRNAs, and 41 mRNAs. Collectively, our study will contribute to improving the understanding of the lncRNA-associated ceRNA network regulatory mechanisms in the pathogenesis of gastric cancer and provide and identify novel lncRNAs as candidate prognostic biomarkers or potential therapeutic targets.

A multi-center phase II study and biomarker analysis of combined cetuximab and modified FOLFIRI as second-line treatment in patients with metastatic gastric cancer.

BACKGROUND: To evaluate the efficacy of cetuximab combined with modified FOLFIRI (mFOLFIRI) as a second-line treatment in metastatic gastric cancer patients and to identify potential biomarkers of clinical outcomes. METHODS: All 61 patients received an initial intravenous (IV) dose of cetuximab (400 mg/m2) and weekly doses (250 mg/m2) thereafter, starting on day 1. On day 2 of each 14-day period, patients received IV irinotecan (180 mg/m2), leucovorin (200 mg/m2), and an IV bolus dose of 5-FU (400 mg/m2) followed by a continuous infusion of 5-FU (2400 mg/m2) for 46 h. The primary endpoint was time-to-progression (TTP). RESULTS: The response rate (RR) was 33.3% among 54 evaluable patients. In the intention-to-treat analysis, median TTP was 4.6 months (95% confidential interval [CI]: 3.6-5.6 months) and median overall survival (OS) was 8.6 months (95% CI: 7.3-9.9 months). In univariate analyses, plasma vascular endothelial growth factor (VEGF) levels were correlated with clinical outcome. In patients with low (≤12.6 pg/ml) and high (>12.6 pg/ml) baseline plasma VEGF levels, RR values were 55.0% and 5.3%, respectively (P = 0.001); median TTP values were 6.9 months and 2.8 months, respectively (P = 0.0005); and median OS values were 12 months and 5 months, respectively (P <0.0001). None of these patients exhibited KRAS, BRAF, or PIK3CA mutations. CONCLUSIONS: Combination therapy comprising cetuximab and mFOLFIRI was well tolerated and active as a second-line treatment for patients with metastatic gastric cancer. Patients with low baseline plasma VEGF levels were associated with better clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov. NCT00699881 . Registered 17 June 2008 (retrospectively registered).

Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy.

BACKGROUND: Programmed cell death 1 (PD-1) is a key cell-surface receptor of CD28 superfamily that triggers inhibitory pathways to attenuate T-cell responses and promote T-cell tolerance. As a crucial role in tumor immunity, PD-1 has been a focus of studies in anti-cancer therapy. It has been approved that tumors could exploit PD-1-dependent immune suppression for immune evasion. Considering the wide use of glucocorticoids (GCs) in anti-cancer therapy and their immunosuppressive effects, we explored whether GCs could influence the expression of PD-1. RESULTS: In our study, we used dexamethasone (DEX) as a model glucocorticoid and demonstrated that DEX could enhance PD-1 expression in a dose-dependent manner. The effects were completely inhibited by the glucocorticoid receptor (GR) antagonist mifepristone (RU486), indicating that the effect of DEX on PD-1 is mediated through GR. We further found the sensitivity to DEX-induced upregulation of PD-1 expression had a significant difference between different T cell subsets, with memory T cells more susceptible to this effect. We also showed that DEX could suppress T cell functions via inhibition of cytokines production such as IL-2, IFN-γ, TNF-α and induction of apoptosis of T cells. CONCLUSION: Our findings suggest a novel way by which DEX suppress the function of activated T lymphocytes by enhancing expression of PD-1 and provide an insight into the optimum clinical application of GCs.

Decreased expression of RPS15A suppresses proliferation of lung cancer cells.

Lung cancer is the leading cause of cancer-related death in the world. Previous report has identified ribosomal protein s15a (RPS15A) as a TGF-ß-responsible gene in the lung adenocarcinoma cell line A549. In this study, we used specific si-RNA to downregulate RPS15A expression in A549 cells and found that decreased RPS15A expression significantly inhibited cell proliferation and survival, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Moreover, A549 cells were obviously accumulated in the G0/G1 phase in response to RPS15A knockdown, suggesting that RPS15A inhibition could induce a diminution of proliferation through cell cycle arrest. In addition, immunohistochemistry analysis further revealed that RPS15A was overexpressed in surgically resected lung cancer tissues. In conclusion, we identify RPS15A as a novel potential oncogenic gene involved in lung carcinogenesis. This study may provide a preliminary experimental basis for a gene therapy approach for treating lung cancer.

Safety and efficacy of nimotuzumab in combination with radiotherapy for patients with squamous cell carcinoma of the esophagus.

BACKGROUND: We investigated nimotuzumab (h-R3), a humanized monoclonal antibody against epidermal growth factor receptor, when combined with irradiation or chemoradiation for squamous cell carcinoma (SCC) of the esophagus. The aim of this study was to evaluate its safety and efficacy. METHODS: We retrospectively analyzed 66 patients with esophageal SCC treated with a combination of h-R3 and radiation or chemoradiation between December 2008 and September 2011 at Fudan University Shanghai Cancer Center. Fifty-two of the 66 patients received h-R3 combined with chemoradiation and 14 received h-R3 plus radiation. The median total irradiation dose was 61 Gy given by conventional fractionation. The h-R3 weekly dosage was 100 mg (6/66), 200 mg (54/66), or 400 mg (6/66) given concurrently during the irradiation period. RESULTS: Patients tolerated the treatment well. Grade 3-4 adverse events and toxicities occurred in 50 % of the patients. h-R3-related toxicities manifested as Grade 1 skin rash in 1 case and Grade 2 infusion-related reaction in 2 cases. The median overall survival (OS) and progression-free survival (PFS) were 26.0 months and 16.7 months, respectively. OS, PFS and locoregional control (LC) at 2 years were 54, 37 and 80 %, respectively. CONCLUSIONS: h-R3 in combination with irradiation or chemoradiation was safe and tolerable, and yielded encouraging OS, PFS and LC.

A novel neoadjuvant therapy for early-stage non-small cell lung cancer in a mouse model.

Background: Lung cancer is the common malignancy with high mortality rate in the world. Even with curative resection for early-stage lung cancer patients, the rate of postoperative recurrence and metastasis is still high. Neoadjuvant nivolumab combined with chemotherapy leads to improved pathological complete response rate and event-free survival in resectable non-small cell lung cancer (NSCLC) patients. However, the neoadjuvant therapy is not only accompanied by grade 3 or above adverse events which resulting in the potential missing out on the window for curative surgery for the patients, but also has low efficacy especially in patients with low programmed death ligand 1 (PD-L1) expression. Hence, it is particularly important to explore innovative ways to inhibit tumour recurrence and metastasis. Methods: In the present study, we investigated whether neoadjuvant therapy with intralesional Rose Bengal (RB) elicited specific immune responses compared with control group, and then the lung cancer mouse model was used to evaluated the immunological mechanism. Results: The secondary Lewis lung cancer cells (LLCs) tumour growth was significantly suppressed by RB intralesional injection into subcutaneous tumour; the formation rate of secondary tumours induced by the B16 melanoma cell injection was 100%. Intralesional RB neoadjuvant therapy before surgical resection exhibited effectively enhanced T central memory cells (Tcm) and T memory stem cells (Tscm) + naïve T cells (Tn) infiltration, elicited stronger cytotoxic T lymphocyte (CTL) responses against LLCs, and displayed markedly higher proportions of splenic lymphocytes that produce tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) upon restimulation in a lung cancer mouse model. Conclusions: Based on our preclinical data, neoadjuvant therapy with intralesional RB injection generated immune memory and prevented the recurrence and metastasis of tumour in a lung cancer mouse model, which provides a new strategy for neoadjuvant treatment of early-stage NSCLC.

Plasma extracellular vesicle long RNA profiling identifies a predictive signature for immunochemotherapy efficacy in lung squamous cell carcinoma.

Introduction: The introduction of Immune Checkpoint Inhibitors (ICIs) has marked a paradigm shift in treating Lung Squamous Cell Carcinoma (LUSC), emphasizing the urgent need for precise molecular biomarkers to reliably forecast therapeutic efficacy. This study aims to identify potential biomarkers for immunochemotherapy efficacy by focusing on plasma extracellular vesicle (EV)-derived long RNAs (exLRs). Methods: We enrolled 78 advanced LUSC patients undergoing first-line immunochemotherapy. Plasma samples were collected, and exLR sequencing was conducted to establish baseline profiles. A retrospective analysis was performed on 42 patients to identify differentially expressed exLRs. Further validation of the top differentially expressed exLRs was conducted using quantitative reverse transcription PCR (qRT-PCR). Univariate Cox analysis was applied to determine the prognostic significance of these exLRs. Based on these findings, we developed a predictive signature (p-Signature). Results: In the retrospective analysis of 42 patients, we identified 460 differentially expressed exLRs, with pathways related to leukocyte migration notably enriched among non-responders. Univariate Cox analysis revealed 45 exLRs with prognostic significance. The top 6 protein-coding exLRs were validated using qRT-PCR, identifying CXCL8, SSH3, and SDHAF1 as differentially expressed between responders and non-responders. The p-Signature, comprising these three exLRs, demonstrated high accuracy in distinguishing responders from non-responders, with an Area Under the Curve (AUC) of 0.904 in the retrospective cohort and 0.812 in the prospective cohort. Discussion: This study highlighted the potential of plasma exLR profiles in predicting LUSC treatment efficacy. Intriguingly, lower p-Signature scores were associated with increased abundance of activated CD4+ and CD8+ T cells, indicating a more robust immune environment. These findings suggest that the p-Signature could serve as a valuable tool in guiding personalized and effective therapeutic strategies for LUSC.

Neoadjuvant chemoimmunotherapy for locally advanced esophageal squamous cell carcinoma: Data from literature review and a real-world analysis.

BACKGROUND: Neoadjuvant chemoimmunotherapy (NCIT) for locally advanced esophageal squamous cell carcinoma (ESCC) is supported by increasing data, but the sample size is limited, and the findings are not completely consistent. We conducted a real-world study and a meta-analysis to evaluate the efficacy and safety of NCIT in locally advanced ESCC. METHODS: We retrospectively assessed the outcomes of patients with locally advanced ESCC who completed NICT and subsequent esophagectomy at our hospital between January 2019 and December 2022, including pathological complete response (pCR) rate, major pathological response (MPR) rate, 1-, 2-, and 3-year overall survival (OS) rates, disease control rate (DCR), objective response rate (ORR), 1-year recurrence rate, R0 resection rate and adverse events. Moreover, a meta-analysis of 27 published literatures was also conducted for comparison. RESULTS: In the analysis, 128 patients were studied, with 25% achieving pCR, 46.1% MPR, and 99.2% R0 resection. The 1-, 2-, and 3-year OS rates were 91.41% (95% CI: 85.15%-95.63%), 75.00% (95% CI: 66.58%-82.23%) and 64.84% (95% CI: 55.91%-73.07%).ORR and DCR were 31.2% (95% CI: 23.31-39.99) and 64.1% (95% CI: 55.15%-72.38%), and the 1-year recurrence rate was 26.7% (95% CI: 22.5%-38.1%). Treatment-related events occurred in 96.1% but were acceptable. In a meta-analysis of 27 studies with 1734 patients, pooled rates for pCR, MPR, ORR, DCR, and R0 resection were 29%, 52%, 71%, 97%, and 98%, respectively, with a 1-year recurrence rate of 12%. CONCLUSION: NCIT is safe and provides potential survival benefits for patients with locally advanced ESCC. However, randomized phase 3 trial data is still needed.

Incidence of and risk factors for suspected and definitive glaucoma after bilateral congenital cataract surgery: a 5-year follow-up.

AIMS: To report the incidence and associated risk factors for developing suspected and definitive glaucoma after bilateral congenital cataract (CC) removal with a 5-year follow-up. METHODS: Secondary analysis of a prospective longitudinal cohort study. Bilateral CC patients who had undergone cataract surgery between January 2011 and December 2014 at Zhongshan Ophthalmic Centre were recruited. Suspected glaucoma was defined as persistent ocular hypertension requiring medical treatment. Definitive glaucoma was defined as accompanied by the progression of glaucomatous clinical features. According to postoperative lens status in 5 years follow-up: 130 eyes in the aphakia group; 219 in the primary intraocular lens (IOL) implantation group and 337 in the secondary IOL implantation group. The Kaplan-Meier survival and Cox regression analyses were used to explore the cumulative incidence and risk factors for suspected and definitive glaucoma. RESULTS: Three hundred fifty-one children (686 eyes) with bilateral CCs were enrolled in the study. The mean age at surgery was 1.82±2.08 years, and the mean follow-up duration was 6.26±0.97 years. Suspected and definitive glaucoma developed at a mean time of 2.84±1.75 years (range 0.02-7.33 years) postoperatively. The cumulative incidence of suspected and definitive glaucoma was 9.97% (35 of 351 patients), including 6.12% (42 eyes) for definitive glaucoma and 2.48% (17 eyes) for suspected glaucoma. Microcornea (HR 4.103, p<0.0001), CC family history (HR 3.285, p=0.001) and initial anterior vitrectomy (HR 2.365 p=0.036) were risk factors for suspected and definitive glaucoma. Gender, age at surgery, intraocular surgery frequency, length of follow-up and frequency of neodymium-doped yttrium aluminumaluminium garnet laser were non-statistically significant. Primary IOL implantation was a protective factor (HR 0.378, p=0.007). CONCLUSIONS: Identifying suspected and definitive glaucoma after bilateral CC surgery can lower the risk of secondary blindness in children. Patients with related risk factors need to pay more attention and thus reach early intervention and treatment during clinical practice. Primary IOL implantation may be a potential protective factor, need more clinical trials to be verified. TRIAL REGISTRATION NUMBER: NCT04342052.